The abnormal acid-base transport within the tubules cannot be solely explained by decreased a glomerular filtration rate (GFR) secondary to chronic kidney disease, obstructive uropathy, or some other non-specific nephropathic mechanism

The precise pathophysiological mechanism underlying the disorder varies across RTA sub-types (I-IV), which are described in detail below.

Normal Acid-Base Homeostasis within the Renal Tubules

Acid-base handling in the renal tubule can be broken down into two stages:

The reabsorption of filtered bicarbonate in the proximal tubule depends on the activity of carbonic anhydrase and several transporters:

Intracellular carbonic anhydrase (CA-II) creates carbonic acid from water and carbon dioxide, which in turn ionizes to form a hydrogen ion plus bicarbonate

The newly created bicarbonate is passively transported into the blood along with sodium by the co-transporter NBC-1

The newly created hydrogen ion is excreted into the tubule by NHE-3, which is driven by the anti-transport of sodium (down its concentration gradient)

Intraluminal carbonic anhydrase (CA-IV) combines the intraluminal bicarbonate and hydrogen ion into water and CO2, the latter of which diffuses back into the cell (and is used as substrate for CA-II), thus driving a net absorption of bicarbonate

This designation is controversial, as most patients appear to have a predominant RTA type I with occasional proximal findings

Hypoaldosteronism (Type IV):

​Caused by either decreased aldosterone concentration or a decreased response of the alpha-intercalating cells to the hormone.

Aldosterone promotes acidification of the urine through multiple mechanisms, which include maintaining a negative intraluminal electrical gradient (promoting proton excretion) and increasing the expression of carbonic anhydrase and the vacuolar H+-ATPase in the alpha-intercalating cells.

Treatment

The goal of treatment for RTA is to correct the underlying acidosis with alkali supplementation (generally a mixture sodium bicarbonate and potassium citrate) in order to maximize growth and development.

However, the individual sub-types of RTA may require additional or modified treatment regimens depending on the underlying etiology:

An RTA secondary to primary hypoaldosteronism can be corrected with exogenous fludrocortisone

Type II RTA secondary to cystinosis (one form of Fanconi’s syndrome) can be treated with cysteamine, a compound that helps break down intracellular cystine.